SOCRATES
PubMed • Full text • PDF
Clinical Question
In patients with acute stroke or transient ischemic attack (TIA), is antiplatelet therapy with ticagrelor superior to aspirin in preventing short-term recurrent stroke, MI or death?
Bottom Line
In patients with acute stroke or TIA, ticagrelor is not clearly superior to aspirin in preventing recurrent stroke, MI, or death at 90 days, although there was a marginally significant 1% absolute reduction in ischemic stroke with ticagrelor. Bleeding rates were similar with both agents.
Major Points
Ischemic stroke and TIA are common, and risk of recurrent cerebrovascular events is very high in the acute post-stroke period. On the strength of multiple large randomized trials demonstrating benefit in reducing recurrent events, consensus AHA/ASA guidelines recommend initiation of aspirin therapy in all patients presenting with acute ischemic stroke or TIA.[1] Even with aspirin therapy, however, the rate of recurrent stroke is still 15-20% within the first 90 days after an acute stroke or TIA. As a result, it is believed that more intense antiplatelet therapy may provide additional benefit in terms of prevention of recurrent ischemic events. Along these lines, the recent CHANCE trial demonstrated that in a large population of Chinese patients presenting with acute minor stroke or TIA, upfront dual antiplatelet therapy with aspirin and clopidogrel provided a 3.5% absolute reduction in recurrent neurologic ischemic events at 90 days.
Ticagrelor, a novel thienopyridine agent in the same class as clopidogrel, is a potent antiplatelet agent that unlike clopidogrel does not rely on genetically variable metabolic activation to provide therapeutic effect. Ticagrelor had recently been shown to be superior to clopidogrel in reducing cardiovascular events in patients presenting with acute coronary syndrome in the PLATO trial. Given its potent and reliable antiplatelet activity, whether ticagrelor could have a role in reducing recurrent events in patients presenting with acute stroke or TIA was an open question requiring further investigation.
The 2016 Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial was designed to investigate the comparative efficacy of ticagrelor versus aspirin in reducing a composite endpoint of recurrent stroke, MI, or death at 90 days in patients presenting with acute neurologic ischemia. SOCRATES randomized 13,000 acute ischemic stroke/TIA patients to either ticagrelor or aspirin. Notably, patients undergoing thrombolysis/thrombectomy or those being given anticoagulation or dual-antiplatelet therapy were excluded. At 90 days, ticagrelor use was associated with only a marginal 1% absolute reduction in the primary endpoint, driven primarily by a 1% reduction in ischemic stroke that was borderline statistically significant. Interestly, rates of major bleeding were low (0.5% with ticagrelor and 0.6% with aspirin) and similar in both groups, although a slightly greater number of patients randomized to ticagrelor discontinued study drug due to minor bleeding events. The results of SOCRATES suggest that ticagrelor is not clearly superior to aspirin in reducing recurrent ischemic events in the post-stroke period, although the marginal benefit of ticagrelor in reducing recurrent stroke suggests that there may be a small increase in thrombotic protection with ticagrelor. In addition, given limited enrollment of patients at particularly high stroke risk and a limited duration of follow up of 90 days, a longer-term benefit with ticagrelor or greater benefit in patients at very high stroke risk cannot be ruled out. Ultimately, despite SOCRATES being a "negative" trial, given similar bleeding rates in both groups, use of ticagrelor instead of aspirin in acute stroke may emerge as a reasonable option, particularly in patients felt to be at particularly high risk for ischemic events.
Guidelines
As of August 2016, no guidelines have been published that reflect the results of this trial.
Design
- Multicenter, randomized, double-blind, double-dummy, parallel-group trial
- N=13,199
- Ticagrelor (n=6589)
- Aspirin (n=6610)
- Setting: 674 sites in 33 countries
- Period: January 7, 2014 - October 29, 2015
- Analysis: Intention-to-treat
- Duration of follow-up: 90 days
- Primary outcome: Stroke, myocardial infarction, or death
Population
Inclusion Criteria
- Either of:
- Acute ischemic stroke with an NIH Stroke Scale score of 5 or lower
- High risk TIA with ABCD2 stroke of 4 or greater OR symptomatic intracranial or extracranial arterial stenosis
- Could undergo randomization within 24 hours of symptom onset
- Age ≥40 years
- Underwent MRI or CT scan ruling out intracranial hemorrhage or non-ischemic etiology of neurologic symptoms
Exclusion Criteria
- Planned use of antithrombotic therapy in addition to study medication
- Receipt or requirement for dual-antiplatelet therapy
- Hypersensitivity to ticagrelor or aspirin
- History of AF, ventricular aneurysm, or suspicion of cardioembolic pathology for TIA or stroke
- Planned carotid, cerebrovascular, or coronary revascularization that requires halting study medication within 7 days of randomization
- Receipt of IV or intra-arterial thrombolysis or mechanical thrombectomy within 24 hours prior to randomization
- Anticipated concomitant oral or IV therapy with strong CYP3A inhibitors or substrates with narrow therapeutic indices that cannot be stopped for the course of the study
- Anticipated requirement for long-term NSAID use
- Known bleeding diathesis or coagulation disorder
- History of previous symptomatic non-traumatic intracerebral bleeding at any time, GI bleeding within past 6 months, or major surgery within 30 days
- Known severe liver disease
- Renal failure requiring dialysis
- Pregnancy or lactation
- Participation in another clinical trial with an investigational product during the last 30 days
Baseline Characteristics
From the ticagrelor group.
- Demographics: Mean age 66 years, male 58.1%, white 66.4%
- Region: Asia/Australia 30.2%, Europe 57.2%, North America 7.8%, Central/South America 4.8%
- Co-morbidities: HTN 72.8%, Dyslipidemia 38.4%, DM 25.3%, BMI 26.1, MI 4.2%, CAD 8.7%, CHF 3.6%
- Neurologic: Previous stroke 11.6%, Previous TIA 6.2%
- Medications: Chronic aspirin 32.3%, Chronic clopidogrel 3.3%
- Event Characteristics: < 12 hrs of symptoms 36.4%, index TIA 27.2%, index stroke 72.8%, baseline ABCD2 score > 5 26.3%, baseline NIH SS > 3 32.1%
Interventions
- All patients presented with acute minor stroke or high risk TIA with symptom onset within preceding 24 hours
- Patients then randomized 1:1 to ticagrelor (180MG load followed by 90MG BID) or aspirin (300MG load followed by 100MG QD)
- At the end of 90 days of study treatment, patients were treated at the discretion of the investigator and followed for an additional 30 days
Outcomes
Comparisons are ticagrelor versus aspirin
Primary Outcome
- Recurrent stroke, MI, or death
- 442 (6.7%) vs. 497 (7.5%) [HR 0.89; 95% CI 0.78-1.01; P=0.07]
Secondary Outcomes
- Ischemic stroke
- 385 (5.8%) vs. 441 (6.7%) [HR 0.87; 95% CI 0.76-1.00; P=0.046]
- Net clinical outcome (stroke, MI, death, or life-threatening bleeding)
- 6.9% vs. 7.7% [HR 0.90; 95% CI 0.79-1.02; P=NS]
Subgroup Analysis
There were no treatment-by-subgroup interactions in the prespecified subgroups (P>0.05 for all comparisons)
Adverse Events
- PLATO-defined major bleeding
- 31 (0.5%) vs. 38 (0.6%) [HR 0.83; 95% CI 0.52-1.34; P=NS]
- Intracranial hemorrhage
- 12 (0.2%) vs. 18 (0.3%)
- Fatal bleeding
- 9 (0.1%) vs. 4 (0.1%)
- Dyspnea
- 6.2% vs. 1.4%
Criticisms
- Study excluded many patients at particularly high risk for stroke, such as those with high-grade carotid or severe intracranial stenosis as these patients were likely to have undergone vascular intervention or dual antiplatelet therapy. These patients would be most likely to benefit from more intense antiplatelet therapy and thus this may have underestimated the benefit of ticagrelor in the post-stroke population.
- Results not generalizable to patients undergoing thrombolysis or thrombectomy as these patients were excluded.
- Primary outcome rates lower than expected in the TIA subgroup, suggesting that some patients may have been misclassified as having had a TIA, which would underestimate any incremental thrombotic protection afforded by ticagrelor.
- Limited duration of follow up cannot exclude a longer-term benefit of ticagrelor therapy.
Funding
- Study sponsor AstraZeneca collaborated in the execution of the trial and collected the data. Analysis was performed by AstraZeneca under the direction of the executive committee.